There is a growing body of evidence indicating the various forms of psychological stress as well as use of drugs such as the opioids can compromise immunologic function, and thus may act as cofactors in HIV progression. The objective of our research is to examine conditioned alterations in immune function induced by an aversive event (electric shock) or by opiate administration, and examine the receptor-mechanisms that play a role in those immunomodulatory effects. Our prior studies with rodents successfully demonstrated that a stimulus which has been paired with (or conditioned to) electric shock can itself induce pronounced and reproducible alterations in immune function. The first specific aim is to extend our investigations of immune alterations induced by a conditioned aversive stimulus. We plan to identify conditioned alterations in the number of T-helper and T-suppressor lymphocytes, B-lymphocytes, and natural killer cells in blood, spleen, and lymph nodes with flow cytometric analysis. We also propose to evaluate the effect of a conditioned stimulus on the in-vivo production of T-dependent and T-independent antibody. The second specific aim expands our investigation to include a different form of conditioning. Given the relationship between opioid drug use and HIV progression, and the fact that morphine represents a "positive" or appetitive rather than aversive stimulus, we will focus our investigations on conditioned morphine-induced alterations of immune function. Our preliminary work has indicated that stimuli paired with morphine administration can induce alterations of immune function, and the proposed plan is to conduct extensive assessments of these conditioned immune alterations. The third specific aim investigates the mechanism by which aversive and appetitive conditioned stimuli induce immune alterations by using standard pharmacological procedures for determining receptor mediation. The experiments proposed are based on ongoing investigations which indicate that both the opioid and beta-adrenergic systems are involved in conditioned immunomodulation. Those investigations have shown that administration of the opiate antagonist naltrexone prior to the presentation of the conditioned aversive stimulus dose-dependently blocked the reduction in the proliferative response of lymphocytes and the suppression of natural killer cell activity. Similarly, administration of the nonselective beta-adrenergic receptor antagonist propranolol blocked the reduction in the proliferative response of lymphocytes. We now propose to identify the subpopulation of receptors which play a role in these conditioned immunomodulatory effects by examining several more selective opioid and beta-adrenergic antagonists. In the opioid system, these include beta-funaltrexamine, an irreversible mu antagonist; nor- binaltorphimine, a kappa selective antagonist; naltrindole, a delta selective antagonist, and quaternary forms of naltrexone. In the beta- adrenergic system, these include the beta2 selective antagonist ICI-118- 551, and beta1 selective antagonists atenolol and metoprolol. The conduct of this research promises to enhance our knowledge of the complex interaction between the central nervous system and the immune system, and the escalating incidence of HIV infection makes urgent the need for this knowledge.